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Gembillo G, Sessa C, Santoro D. Advances in the pathophysiology and treatment of focal segmental glomerulosclerosis: The importance of a timely and tailored approach. World J Nephrol 2025; 14. [DOI: 10.5527/wjn.v14.i2.103039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 01/14/2025] [Accepted: 01/21/2025] [Indexed: 04/09/2025] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular damage that significantly contributes to chronic kidney disease and end-stage renal disease. Its incidence is rising globally, necessitating timely and personalized management strategies. This paper aims to provide an updated overview of the pathophysiology, diagnosis, and therapeutic strategies for FSGS, emphasizing the importance of early interventions and tailored treatments. This editorial synthesizes key findings from recent literature to highlight advancements in understanding and managing FSGS. Emerging evidence supports the role of targeted therapies and personalized approaches in improving outcomes for FSGS patients. Advances include novel biomarkers, genetic testing, and innovative therapeutics such as transient receptor potential ion channel blockers and antisense oligonucleotides for apolipoprotein 1-related FSGS. Effective management of FSGS requires a combination of timely diagnosis, evidence-based therapeutic strategies, and ongoing research to optimize patient outcomes and address gaps in the current understanding of the disease.
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Affiliation(s)
- Guido Gembillo
- Unit of Nephrology and Dialysis, AOU "G. Martino", University of Messina, Messina 98125, Sicilia, Italy
| | - Concetto Sessa
- Unit of Nephrology and Dialysis, P.O. Maggiore "Nino Baglieri", Ragusa 97100, Sicilia, Italy
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, AOU "G. Martino", University of Messina, Messina 98125, Sicilia, Italy
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Horinouchi T, Nozu K, Iijima K. Genetic aspects of pediatric nephrotic syndrome and anti-nephrin antibodies. Clin Exp Nephrol 2025; 29:534-540. [PMID: 40085383 PMCID: PMC12049277 DOI: 10.1007/s10157-025-02645-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 02/14/2025] [Indexed: 03/16/2025]
Abstract
Nephrotic syndrome is the most common glomerular disease in children, and various hypotheses regarding its etiology have been proposed, primarily focusing on immune-related mechanisms. Nephrotic syndrome can manifest as a monogenic disease caused by deleterious variants in genes such as NPHS1, which encodes nephrin. In steroid-sensitive nephrotic syndrome, HLA class II and immune-related genes have been identified as susceptibility genes. Moreover, NPHS1 is a susceptibility gene for steroid-sensitive nephrotic syndrome in patients from East Asian populations. Anti-nephrin antibodies have been identified as a significant factor in the pathogenesis of nephrotic syndrome. These discoveries have substantially advanced our understanding of nephrotic syndrome. However, the mechanisms underlying the production of anti-nephrin antibodies and their association with genetic backgrounds have remained unclear and warrant further investigation.
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Affiliation(s)
- Tomoko Horinouchi
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Kazumoto Iijima
- Hyogo Prefectural Kobe Children's Hospital, Hyogo, Japan
- Department of Advanced Pediatric Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
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Robinson CH, Smoyer WE, Cara-Fuentes G. Unraveling the Immunogenetic Mechanisms of Childhood Idiopathic Nephrotic Syndrome. J Pediatr 2025; 282:114595. [PMID: 40252964 DOI: 10.1016/j.jpeds.2025.114595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/16/2025] [Accepted: 04/14/2025] [Indexed: 04/21/2025]
Affiliation(s)
- Cal H Robinson
- Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada; Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.
| | - William E Smoyer
- The Center for Clinical and Translational Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH; Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH
| | - Gabriel Cara-Fuentes
- Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH
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Zhu Y, Xu G. Advances in Focal Segmental Glomerulosclerosis Treatment From the Perspective of the Newest Mechanisms of Podocyte Injury. Drug Des Devel Ther 2025; 19:857-875. [PMID: 39935575 PMCID: PMC11812565 DOI: 10.2147/dddt.s498457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 12/19/2024] [Indexed: 02/13/2025] Open
Abstract
Podocyte injury was widely recognized as a fundamental mechanism driving the progression of focal segmental glomerulosclerosis (FSGS). Recent research has therefore focused on the development of targeted therapies aimed at disrupting specific pathogenic signaling cascades within podocytes, resulting in noteworthy advancements. The role of mechanisms such as alterations in the actin cytoskeleton, oxidative stress, mitochondrial dysfunction, and inadequate autophagy within the microenvironment of podocyte injury have garnered increasing attention. Corresponding targeted medications such as Abatacept, chemokine receptor (CCR) inhibitors, CDDO-Im (2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide), adenosine monophosphate-activated protein kinase (AMPK) activators, and Adalimumab are currently under investigation. Notably, some medications such as Rituximab and Sparsentan, may simultaneously target multiple downstream mechanisms, Furthermore, exploring molecular strategies for established medications and developing novel treatments guided by biomarkers such as Anti-CD40 antibody, blood microRNA, urinary microRNA, and tumor necrosis factor-alpha (TNF-α) may provide additional therapeutic avenues for patients with FSGS.
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Affiliation(s)
- Yan Zhu
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
- Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
| | - Gaosi Xu
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
- Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
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Di Carlo S, Longhitano E, Spinella C, Maressa V, Casuscelli C, Peritore L, Santoro D. Traditional, alternative, and emerging therapeutics for focal segmental glomerulosclerosis. Expert Opin Pharmacother 2025; 26:179-186. [PMID: 39743782 DOI: 10.1080/14656566.2024.2446621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 12/20/2024] [Indexed: 01/04/2025]
Abstract
INTRODUCTION Segmental focal glomerulosclerosis is a histological lesion characterized by podocyte damage. It may be a primary disease linked to an unknown circulating factor, secondary to viral infections, drug toxicity, or a disadaptive response to the loss of nephrons, or it may depend on gene mutations or have an indeterminate cause. The treatment of the primary form involves immunosuppressors. Additional pharmacotherapies for residual proteinuria are used, and emerging therapies are being studied to target other pathological pathways. AREAS COVERED This paper covers the treatment of FSGS, focusing on traditional and emerging therapeutic strategies. It is based on the KDIGO 2021 guidelines and supplemented by a literature search conducted on PubMed. EXPERT OPINION Treating FSGS is challenging due to its heterogeneity. Immunosuppression is adequate for primary FSGS but harmful in genetic or secondary forms. Key strategies include targeting the underlying cause and using agents that affect renal hemodynamics. Antifibrotic drugs can help slow kidney damage by addressing chronic inflammation and fibrosis. Alongside pharmacological treatments, managing blood pressure and restricting dietary salt are crucial. Finally, personalized treatment requires stratifying patients based on clinical, genetic, and histological data to improve clinical trial design and outcomes.
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Affiliation(s)
- Silvia Di Carlo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, A.O.U. "G.Martino", University of Messina, Messina, Italy
| | - Elisa Longhitano
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, A.O.U. "G.Martino", University of Messina, Messina, Italy
| | - Claudia Spinella
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, A.O.U. "G.Martino", University of Messina, Messina, Italy
| | - Veronica Maressa
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, A.O.U. "G.Martino", University of Messina, Messina, Italy
| | - Chiara Casuscelli
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, A.O.U. "G.Martino", University of Messina, Messina, Italy
| | - Luigi Peritore
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, A.O.U. "G.Martino", University of Messina, Messina, Italy
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, A.O.U. "G.Martino", University of Messina, Messina, Italy
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Zununi Vahed S, Hosseiniyan Khatibi SM, Ardalan M. Canonical effects of cytokines on glomerulonephritis: A new outlook in nephrology. Med Res Rev 2025; 45:144-163. [PMID: 39164945 DOI: 10.1002/med.22074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 08/28/2022] [Accepted: 08/04/2024] [Indexed: 08/22/2024]
Abstract
Glomerulonephritis (GN) is an important cause of renal inflammation resulting from kidney-targeted adaptive and innate immune responses and consequent glomerular damage. Given the lack of autoantibodies, immune complexes, or the infiltrating immune cells in some forms of GN, for example, focal segmental glomerulosclerosis and minimal change disease, along with paraneoplastic syndrome and a special form of renal involvement in some viral infections, the likeliest causative scenario would be secreted factors, mainly cytokine(s). Since cytokines can modulate the inflammatory mechanisms, severity, and clinical outcomes of GN, it is rational to consider the umbrella term of cytokine GN as a new outlook to reclassify a group of previously known GN. We focus here, particularly, on cytokines that have the central "canonical effect" in the development of GN.
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Altintas MM, Agarwal S, Sudhini Y, Zhu K, Wei C, Reiser J. Pathogenesis of Focal Segmental Glomerulosclerosis and Related Disorders. ANNUAL REVIEW OF PATHOLOGY 2025; 20:329-353. [PMID: 39854184 PMCID: PMC11875227 DOI: 10.1146/annurev-pathol-051220-092001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
Focal segmental glomerulosclerosis (FSGS) is the morphologic manifestation of a spectrum of kidney diseases that primarily impact podocytes, cells that create the filtration barrier of the glomerulus. As its name implies, only parts of the kidney and glomeruli are affected, and only a portion of the affected glomerulus may be sclerosed. Although the diagnosis is based primarily on microscopic features, patient stratification relies on clinical data such as proteinuria and etiological criteria. FSGS affects both children and adults and has an elevated risk of progression to end-stage renal disease. The prevalence of FSGS is rising among various populations, and the efficacy of various therapies is limited. Therefore, understanding the pathophysiology of FSGS and developing targeted therapies to address the complex needs of FSGS patients are topics of great interest that are currently being studied across various clinical trials. We discuss the etiology of FSGS, describe the major contributing pathophysiological pathways, and outline emerging therapeutic strategies along with their pitfalls.
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Affiliation(s)
- Mehmet M Altintas
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | | | - Yashwanth Sudhini
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Ke Zhu
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | - Changli Wei
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | - Jochen Reiser
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
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Zhang Y, Yao T, Xu Y, Wang Y, Han S. Circulating RAC1 contributed to steroid-sensitive nephrotic syndrome: Mendelian randomization, single-cell RNA-sequencing, proteomic, and experimental evidence. Ren Fail 2024; 46:2416087. [PMID: 39422242 PMCID: PMC11492449 DOI: 10.1080/0886022x.2024.2416087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 09/19/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024] Open
Abstract
OBJECTIVES The small GTPase Rac1 (RAC1) has been linked to podocyte disorders and steroid-sensitive nephrotic syndrome (SSNS). The aim of this study was to explore and validate the potential causal association between circulating RAC1 and SSNS. METHODS The association between circulating RAC1 and SSNS at both gene expression and proteomic levels was investigated using Mendelian randomization analysis, and further validated by single-cell RNA-sequencing, proteomic analysis, and experimental studies. The genetic instruments comprised cis-expression quantitative trait loci (cis-eQTLs) associated with RAC1 gene expression and protein QTLs correlated with plasma RAC1 protein levels. Causal associations were estimated utilizing the inverse variance weighted and MR-PRESSO methods. Validation of RAC1 expression was conducted through single-cell RNA-sequencing of peripheral blood mononuclear cells from patients with SSNS and healthy controls. Proteomic analysis was performed among patients with minimal change nephrotic syndrome. Experimental validation was conducted using a puromycin aminonucleoside (PAN)-induced nephrosis model. RESULTS Increased expression of RAC1 was associated with a higher risk of SSNS (gene expression level: odds ratio [OR], 1.53; 95% confidence interval [CI], 1.02-2.28; protein level: OR, 1.82; 95% CI, 1.05-3.17). The results of MR-PRESSO were consistent (gene expression level: OR, 1.49; 95% CI, 1.17-1.92; protein level: OR, 1.81; 95% CI, 1.16-2.85). Single-cell RNA sequencing and proteomic analysis confirmed elevated RAC1 expression in patients with SSNS compared to healthy controls. Experimental data further supported increased RAC1 expression in PAN-induced nephropathy. CONCLUSIONS Increased expression of RAC1 might be causally associated with SSNS, suggesting that targeting RAC1 might represent a potential therapeutic strategy for SSNS.
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Affiliation(s)
- Yi Zhang
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tianwen Yao
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yanqiu Xu
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yi Wang
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shisheng Han
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Xie Y, Liu F. Precision medicine for focal segmental glomerulosclerosis. Kidney Res Clin Pract 2024; 43:709-723. [PMID: 38325863 PMCID: PMC11615440 DOI: 10.23876/j.krcp.23.227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 11/06/2023] [Accepted: 11/15/2023] [Indexed: 02/09/2024] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is one of the common causes of nephrotic syndrome in adults and children worldwide. FSGS consists of a group of kidney diseases classified based on specific histopathological features. The current classification of FSGS makes it difficult to distinguish individual differences in pathogenesis, disease progression, and response to treatment. In recent years, the spread of next-generation sequencing, updates in biological techniques, and improvements of treatment have changed our understanding of FSGS. In this review, we will discuss the use of genetic testing in patients with FSGS, explore its clinical significance from a genetic identification perspective, and introduce several new biomarkers, that may help in the early diagnosis of FSGS and guide the development of specific or targeted therapies, so as to understand the biological characteristics in FSGS. This will certainly help develop more effective and safer treatments and advance precision medicine.
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Affiliation(s)
- Yi Xie
- Department of Nephrology, Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Fei Liu
- Department of Nephrology, Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China
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Hou S, Yang B, Chen Q, Xu Y, Li H. Potential biomarkers of recurrent FSGS: a review. BMC Nephrol 2024; 25:258. [PMID: 39134955 PMCID: PMC11318291 DOI: 10.1186/s12882-024-03695-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 08/05/2024] [Indexed: 08/16/2024] Open
Abstract
Focal segmental glomerulosclerosis (FSGS), a clinicopathological condition characterized by nephrotic-range proteinuria, has a high risk of progression to end-stage renal disease (ESRD). Meanwhile, the recurrence of FSGS after renal transplantation is one of the main causes of graft loss. The diagnosis of recurrent FSGS is mainly based on renal puncture biopsy transplants, an approach not widely consented by patients with early mild disease. Therefore, there is an urgent need to find definitive diagnostic markers that can act as a target for early diagnosis and intervention in the treatment of patients. In this review, we summarize the domestic and international studies on the pathophysiology, pathogenesis and earliest screening methods of FSGS and describe the functions and roles of specific circulating factors in the progression of early FSGS, in order to provide a new theoretical basis for early diagnosis of FSGS recurrence, as well as aid the exploration of therapeutic targets.
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Affiliation(s)
- Shuang Hou
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Bo Yang
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Qian Chen
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Yuan Xu
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China.
| | - Haiyang Li
- Hepatological surgery department, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China.
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Matoba K, Nagai Y, Sekiguchi K, Ohashi S, Mitsuyoshi E, Shimoda M, Tachibana T, Kawanami D, Yokota T, Utsunomiya K, Nishimura R. Deletion of podocyte Rho-associated, coiled-coil-containing protein kinase 2 protects mice from focal segmental glomerulosclerosis. Commun Biol 2024; 7:402. [PMID: 38565675 PMCID: PMC10987559 DOI: 10.1038/s42003-024-06127-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 03/29/2024] [Indexed: 04/04/2024] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) shares podocyte damage as an essential pathological finding. Several mechanisms underlying podocyte injury have been proposed, but many important questions remain. Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) is a serine/threonine kinase responsible for a wide array of cellular functions. We found that ROCK2 is activated in podocytes of adriamycin (ADR)-induced FSGS mice and cultured podocytes stimulated with ADR. Conditional knockout mice in which the ROCK2 gene was selectively disrupted in podocytes (PR2KO) were resistant to albuminuria, glomerular sclerosis, and podocyte damage induced by ADR injection. In addition, pharmacological intervention for ROCK2 significantly ameliorated podocyte loss and kidney sclerosis in a murine model of FSGS by abrogating profibrotic factors. RNA sequencing of podocytes treated with a ROCK2 inhibitor proved that ROCK2 is a cyclic nucleotide signaling pathway regulator. Our study highlights the potential utility of ROCK2 inhibition as a therapeutic option for FSGS.
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Affiliation(s)
- Keiichiro Matoba
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
| | - Yosuke Nagai
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Kensuke Sekiguchi
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Shinji Ohashi
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Etsuko Mitsuyoshi
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Masayuki Shimoda
- Department of Pathology, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Toshiaki Tachibana
- Core Research Facilities for Basic Science, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Daiji Kawanami
- Department of Endocrinology and Diabetes, Fukuoka University School of Medicine, Fukuoka, 814-0180, Japan
| | - Tamotsu Yokota
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | | | - Rimei Nishimura
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
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Kovalik ME, Dacanay MA, Crowley SD, Hall G. Swollen Feet: Considering the Paradoxical Roles of Interleukins in Nephrotic Syndrome. Biomedicines 2024; 12:738. [PMID: 38672094 PMCID: PMC11048099 DOI: 10.3390/biomedicines12040738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 04/28/2024] Open
Abstract
Interleukins are a family of 40 bioactive peptides that act through cell surface receptors to induce a variety of intracellular responses. While interleukins are most commonly associated with destructive, pro-inflammatory signaling in cells, some also play a role in promoting cellular resilience and survival. This review will highlight recent evidence of the cytoprotective actions of the interleukin 1 receptor (IL-1R)- and common gamma chain receptor (IL-Rγc)-signaling cytokines in nephrotic syndrome (NS). NS results from the injury or loss of glomerular visceral epithelial cells (i.e., podocytes). Although the causes of podocyte dysfunction vary, it is clear that pro-inflammatory cytokines play a significant role in regulating the propagation, duration and severity of disease. Pro-inflammatory cytokines signaling through IL-1R and IL-Rγc have been shown to exert anti-apoptotic effects in podocytes through the phosphoinositol-3-kinase (PI-3K)/AKT pathway, highlighting the potential utility of IL-1R- and IL-Rγc-signaling interleukins for the treatment of podocytopathy in NS. The paradoxical role of interleukins as drivers and mitigators of podocyte injury is complex and ill-defined. Emerging evidence of the cytoprotective role of some interleukins in NS highlights the urgent need for a nuanced understanding of their pro-survival benefits and reveals their potential as podocyte-sparing therapeutics for NS.
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Affiliation(s)
- Maria E. Kovalik
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
| | - Monique A. Dacanay
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
| | - Steven D. Crowley
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
| | - Gentzon Hall
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
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Catanese L, Rupprecht H, Huber TB, Lindenmeyer MT, Hengel FE, Amann K, Wendt R, Siwy J, Mischak H, Beige J. Non-Invasive Biomarkers for Diagnosis, Risk Prediction, and Therapy Guidance of Glomerular Kidney Diseases: A Comprehensive Review. Int J Mol Sci 2024; 25:3519. [PMID: 38542491 PMCID: PMC10970781 DOI: 10.3390/ijms25063519] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/13/2024] [Accepted: 03/18/2024] [Indexed: 04/09/2025] Open
Abstract
Effective management of glomerular kidney disease, one of the main categories of chronic kidney disease (CKD), requires accurate diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for the assessment of specific aspects of glomerular diseases have been reported in the literature. Though, the vast majority of these have not been implemented in clinical practice or are not available on a global scale due to limited access, missing medical infrastructure, or economical as well as political reasons. The aim of this review is to compile all currently available information on the diagnostic, prognostic, and predictive biomarkers currently available for the management of glomerular diseases, and provide guidance on the application of these biomarkers. As a result of the compiled evidence for the different biomarkers available, we present a decision tree for a non-invasive, biomarker-guided diagnostic path. The data currently available demonstrate that for the large majority of patients with glomerular diseases, valid biomarkers are available. However, despite the obvious disadvantages of kidney biopsy, being invasive and not applicable for monitoring, especially in the context of rare CKD etiologies, kidney biopsy still cannot be replaced by non-invasive strategies.
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Affiliation(s)
- Lorenzo Catanese
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, 95445 Bayreuth, Germany; (L.C.); (H.R.)
- Kuratorium for Dialysis and Transplantation (KfH) Bayreuth, 95445 Bayreuth, Germany
- Department of Nephrology, Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Harald Rupprecht
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, 95445 Bayreuth, Germany; (L.C.); (H.R.)
- Kuratorium for Dialysis and Transplantation (KfH) Bayreuth, 95445 Bayreuth, Germany
- Department of Nephrology, Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Tobias B. Huber
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; (T.B.H.); (M.T.L.); (F.E.H.)
| | - Maja T. Lindenmeyer
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; (T.B.H.); (M.T.L.); (F.E.H.)
| | - Felicitas E. Hengel
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; (T.B.H.); (M.T.L.); (F.E.H.)
| | - Kerstin Amann
- Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Ralph Wendt
- Division of Nephrology, St. Georg Hospital, 04129 Leipzig, Germany;
| | - Justyna Siwy
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany; (J.S.); (H.M.)
| | - Harald Mischak
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany; (J.S.); (H.M.)
| | - Joachim Beige
- Division of Nephrology, St. Georg Hospital, 04129 Leipzig, Germany;
- Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, 06108 Halle, Germany
- Kuratorium for Dialysis and Transplantation (KfH) Leipzig, 04129 Leipzig, Germany
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14
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Shirai Y, Miura K, Ishizuka K, Ando T, Kanda S, Hashimoto J, Hamasaki Y, Hotta K, Ito N, Honda K, Tanabe K, Takano T, Hattori M. A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence. Kidney Int 2024; 105:608-617. [PMID: 38110152 DOI: 10.1016/j.kint.2023.11.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/07/2023] [Accepted: 11/10/2023] [Indexed: 12/20/2023]
Abstract
Possible roles of anti-nephrin antibodies in post-transplant recurrent focal segmental glomerulosclerosis (FSGS) have been reported recently. To confirm these preliminary results, we performed a multi-institutional study of 22 Japanese pediatric kidney transplant recipients with FSGS including eight genetic FSGS and 14 non-genetic (presumed primary) FSGS. Eleven of the 14 non-genetic FSGS patients had post-transplant recurrent FSGS. Median (interquartile range) plasma levels of anti-nephrin antibodies in post-transplant recurrent FSGS measured using ELISA were markedly high at 899 (831, 1292) U/mL (cutoff 231 U/mL) before transplantation or during recurrence. Graft biopsies during recurrence showed punctate IgG deposition co-localized with nephrin that had altered localization with increased nephrin tyrosine phosphorylation and Src homology and collagen homology A expressions. Graft biopsies after remission showed no signals for IgG and a normal expression pattern of nephrin. Anti-nephrin antibody levels decreased to 155 (53, 367) U/mL in five patients with samples available after remission. In patients with genetic FSGS as in those with non-genetic FSGS without recurrence, anti-nephrin antibody levels were comparable to those of 30 control individuals, and graft biopsies had no signals for IgG and a normal expression pattern of nephrin. Thus, our results suggest that circulating anti-nephrin antibodies are a possible candidate for circulating factors involved in the pathogenesis of post-transplant recurrent FSGS and that this may be mediated by nephrin phosphorylation. Larger studies including other ethnicities are required to confirm this finding.
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Affiliation(s)
- Yoko Shirai
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kenichiro Miura
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kiyonobu Ishizuka
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Taro Ando
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | | | - Junya Hashimoto
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Yuko Hamasaki
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Kiyohiko Hotta
- Department of Urology, Hokkaido University, Graduate School of Medicine, Hokkaido, Japan
| | - Naoko Ito
- Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazuho Honda
- Department of Anatomy, Showa University School of Medicine, Tokyo, Japan
| | - Kenji Tanabe
- Medical Research Institute, Tokyo Women's Medical University, Tokyo, Japan
| | - Tomoko Takano
- Division of Nephrology, McGill University Health Centre, Montreal, Québec, Canada
| | - Motoshi Hattori
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
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15
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Lin YC, Gau TS, Jiang ZH, Chen KY, Tsai YT, Lin KY, Tung HN, Chang FC. Targeted therapy in glomerular diseases. J Formos Med Assoc 2024; 123:149-158. [PMID: 37442744 DOI: 10.1016/j.jfma.2023.06.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 05/14/2023] [Accepted: 06/25/2023] [Indexed: 07/15/2023] Open
Abstract
Targeted therapy has emerged as a more precise approach to treat glomerular diseases, focusing on specific molecular or cellular processes that contribute to disease development or progression. This approach complements or replaces traditional immunosuppressive therapy, optimizes supportive care, and provides a more personalized treatment strategy. In this review, we summarize the evolving understanding of pathogenic mechanisms in immune-mediated glomerular diseases and the developing targeted therapies based on these mechanisms. We begin by discussing pan-B-cell depletion, anti-CD20 rituximab, and targeting B-cell survival signaling through the BAFF/APRIL pathway. We also exam specific plasma cell depletion with anti-CD38 antibody. We then shift our focus to complement activation in glomerular diseases, which is involved in antibody-mediated glomerular diseases, such as IgA nephropathy, membranous nephropathy, ANCA-associated vasculitis, and lupus nephritis. Non-antibody-mediated complement activation occurs in glomerular diseases, including C3 glomerulopathy, complement-mediated atypical hemolytic uremic syndrome, and focal segmental glomerulosclerosis. We discuss specific inhibition of terminal, lectin, and alternative pathways in different glomerular diseases. Finally, we summarize current clinical trials targeting the final pathways of various glomerular diseases, including kidney fibrosis. We conclude that targeted therapy based on individualized pathogenesis should be the future of treating glomerular diseases.
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Affiliation(s)
- Yi-Chan Lin
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tyng-Shiuan Gau
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Zheng-Hong Jiang
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kuan-Yu Chen
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Ting Tsai
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kuan-Yu Lin
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hung-Ning Tung
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Fan-Chi Chang
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
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16
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Veltkamp F, Thenot V, Mussies C, van Lieshout B, Peters-Sengers H, Kers J, Khan DH, Hogan J, Florquin S, Bouts AHM, Dossier C. Incidence of idiopathic nephrotic syndrome during the Covid-19 pandemic in the Paris area (France) and in the Netherlands. Pediatr Nephrol 2023; 38:3681-3692. [PMID: 37191940 PMCID: PMC10186275 DOI: 10.1007/s00467-023-06006-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 04/21/2023] [Accepted: 04/21/2023] [Indexed: 05/17/2023]
Abstract
BACKGROUND The aetiology of idiopathic nephrotic syndrome (INS) remains partially unknown. Viral infections have been associated with INS onset. Since we observed fewer first onset INS cases during the Covid-19 pandemic, we hypothesised that lower INS incidence was the result of lockdown measures. Therefore, the aim of this study was to evaluate the incidence of childhood INS before and during the COVID-19 pandemic in two independent European INS cohorts. METHODS Children with new INS in the Netherlands (2018-2021) and Paris area (2018-2021) were included. We estimated incidences using census data for each region. Incidences were compared using two proportion Z-tests. RESULTS A total of 128 and 324 cases of first onset INS were reported in the Netherlands and Paris area, respectively, corresponding to an annual incidence of 1.21 and 2.58 per 100,000 children/year. Boys and young children (< 7 years) were more frequently affected. Incidence before and during the pandemic did not differ. When schools were closed, incidence was lower in both regions: 0.53 vs. 1.31 (p = 0.017) in the Netherlands and 0.94 vs. 2.63 (p = 0.049) in the Paris area. During peaks of hospital admissions for Covid-19, no cases were reported in the Netherlands or Paris area. CONCLUSIONS Incidence of INS before and during the Covid-19 pandemic was not different, but when schools were closed during lockdown, incidence was significantly lower. Interestingly, incidences of other respiratory viral infections were also reduced as was air pollution. Together, these results argue for a link between INS onset and viral infections and/or environmental factors. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Floor Veltkamp
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam, 1109 AZ, The Netherlands.
| | - Victoire Thenot
- Department of Pediatric Nephrology, Robert-Debré Hospital, APHP, Paris, France
| | - Carlijn Mussies
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam, 1109 AZ, The Netherlands
| | - Bas van Lieshout
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam, 1109 AZ, The Netherlands
| | - Hessel Peters-Sengers
- Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Department of Epidemiology and Data Science, VU University Amsterdam, Amsterdam University Medical Center, Amsterdam, Netherlands
| | - Jesper Kers
- Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
- Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands
| | - Djera H Khan
- Department of Epidemiology and Data Science, VU University Amsterdam, Amsterdam University Medical Center, Amsterdam, Netherlands
| | - Julien Hogan
- Department of Pediatric Nephrology, Robert-Debré Hospital, APHP, Paris, France
| | - Sandrine Florquin
- Department of Epidemiology and Data Science, VU University Amsterdam, Amsterdam University Medical Center, Amsterdam, Netherlands
| | - Antonia H M Bouts
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam, 1109 AZ, The Netherlands
| | - Claire Dossier
- Department of Pediatric Nephrology, Robert-Debré Hospital, APHP, Paris, France
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17
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Hayward S, Parmesar K, Saleem MA. What is circulating factor disease and how is it currently explained? Pediatr Nephrol 2023; 38:3513-3518. [PMID: 36952039 PMCID: PMC10514121 DOI: 10.1007/s00467-023-05928-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/15/2023] [Accepted: 02/20/2023] [Indexed: 03/24/2023]
Abstract
Nephrotic syndrome (NS) consists of the clinical triad of hypoalbuminaemia, high levels of proteinuria and oedema, and describes a heterogeneous group of disease processes with different underlying drivers. The existence of circulating factor disease (CFD) as a driver of NS has been epitomised by a subset of patients who exhibit disease recurrence after transplantation, alongside laboratory work. Several circulating factors have been proposed and studied, broadly grouped into protease components such as soluble urokinase-type plasminogen activator (suPAR), hemopexin (Hx) and calcium/calmodulin-serine protease kinase (CASK), and other circulating proteases, and immune components such as TNF-α, CD40 and cardiotrophin-like cytokine-1 (CLC-1). While currently there is no definitive way of assessing risk of CFD pre-transplantation, promising work is emerging through the study of 'multi-omic' bioinformatic data from large national cohorts and biobanks.
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Affiliation(s)
- Samantha Hayward
- Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
| | - Kevon Parmesar
- Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Moin A Saleem
- Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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18
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Salfi G, Casiraghi F, Remuzzi G. Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis. Front Immunol 2023; 14:1247606. [PMID: 37795085 PMCID: PMC10546017 DOI: 10.3389/fimmu.2023.1247606] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 09/05/2023] [Indexed: 10/06/2023] Open
Abstract
The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated. However, a growing body of evidence emphasizes the pivotal role of the immune system in both initiating and perpetuating the disease. Extensive investigations, encompassing both experimental models and patient studies, have implicated T cells, B cells, and complement as crucial actors in the pathogenesis of primary FSGS, with various molecules being proposed as potential "circulating factors" contributing to the disease and its recurrence post kidney-transplantation. In this review, we critically assessed the existing literature to identify essential pathways for a comprehensive characterization of the pathogenesis of FSGS. Recent discoveries have shed further light on the intricate interplay between these mechanisms. We present an overview of the current understanding of the engagement of distinct molecules and immune cells in FSGS pathogenesis while highlighting critical knowledge gaps that require attention. A thorough characterization of these intricate immune mechanisms holds the potential to identify noninvasive biomarkers that can accurately identify patients at high risk of post-transplant recurrence. Such knowledge can pave the way for the development of targeted and personalized therapeutic approaches in the management of FSGS.
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Affiliation(s)
| | - Federica Casiraghi
- Istituto di Ricerche Farmacologiche Mario Negri Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bergamo, Italy
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19
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Vivarelli M, Gibson K, Sinha A, Boyer O. Childhood nephrotic syndrome. Lancet 2023; 402:809-824. [PMID: 37659779 DOI: 10.1016/s0140-6736(23)01051-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 05/04/2023] [Accepted: 05/19/2023] [Indexed: 09/04/2023]
Abstract
Idiopathic nephrotic syndrome is the most common glomerular disease in children. Corticosteroids are the cornerstone of its treatment, and steroid response is the main prognostic factor. Most children respond to a cycle of oral steroids, and are defined as having steroid-sensitive nephrotic syndrome. Among the children who do not respond, defined as having steroid-resistant nephrotic syndrome, most respond to second-line immunosuppression, mainly with calcineurin inhibitors, and children in whom a response is not observed are described as multidrug resistant. The pathophysiology of nephrotic syndrome remains elusive. In cases of immune-mediated origin, dysregulation of immune cells and production of circulating factors that damage the glomerular filtration barrier have been described. Conversely, up to a third of cases of steroid-resistant nephrotic syndrome have a monogenic origin. Multidrug resistant nephrotic syndrome often leads to kidney failure and can cause relapse after kidney transplant. Although steroid-sensitive nephrotic syndrome does not affect renal function, most children with steroid-sensitive nephrotic syndrome have a relapsing course that requires repeated steroid cycles with significant side-effects. To minimise morbidity, some patients require steroid-sparing immunosuppressive agents, including levamisole, mycophenolate mofetil, calcineurin inhibitors, anti-CD20 monoclonal antibodies, and cyclophosphamide. Close monitoring and preventive measures are warranted at onset and during relapse to prevent acute complications (eg, hypovolaemia, acute kidney injury, infections, and thrombosis), whereas long-term management requires minimising treatment-related side-effects. A subset of patients have active disease into adulthood.
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Affiliation(s)
- Marina Vivarelli
- Division of Nephrology, Laboratory of Nephrology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
| | - Keisha Gibson
- Division of Nephrology and Hypertension, University of North Carolina Kidney Center, University of North Carolina at Chapel Hill, NC, USA
| | - Aditi Sinha
- Division of Nephrology, Indian Council of Medical Research Center for Advanced Research in Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Olivia Boyer
- Néphrologie Pédiatrique, Centre de Référence Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Hôpital Necker - Enfants Malades, Assistance Publique Hôpitaux de Paris, Inserm U1163, Institut Imagine, Université Paris Cité, Paris, France
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20
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Vincenti F, Angeletti A, Ghiggeri GM. State of the art in childhood nephrotic syndrome: concrete discoveries and unmet needs. Front Immunol 2023; 14:1167741. [PMID: 37503337 PMCID: PMC10368981 DOI: 10.3389/fimmu.2023.1167741] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/21/2023] [Indexed: 07/29/2023] Open
Abstract
Nephrotic syndrome (NS) is a clinical entity characterized by proteinuria, hypoalbuminemia, and peripheral edema. NS affects about 2-7 per 100,000 children aged below 18 years old yearly and is classified, based on the response to drugs, into steroid sensitive (SSNS), steroid dependent, (SDNS), multidrug dependent (MDNS), and multidrug resistant (MRNS). Forms of NS that are more difficult to treat are associated with a worse outcome with respect to renal function. In particular, MRNS commonly progresses to end stage renal failure requiring renal transplantation, with recurrence of the original disease in half of the cases. Histological presentations of NS may vary from minimal glomerular lesions (MCD) to focal segmental glomerulosclerosis (FSGS) and, of relevance, the histological patterns do not correlate with the response to treatments. Moreover, around half of MRNS cases are secondary to causative pathogenic variants in genes involved in maintaining the glomerular structure. The pathogenesis of NS is still poorly understood and therapeutic approaches are mostly based on clinical experience. Understanding of pathogenetic mechanisms of NS is one of the 'unmet needs' in nephrology and represents a significant challenge for the scientific community. The scope of the present review includes exploring relevant findings, identifying unmet needs, and reviewing therapeutic developments that characterize NS in the last decades. The main aim is to provide a basis for new perspectives and mechanistic studies in NS.
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Affiliation(s)
- Flavio Vincenti
- Division of Nephrology, Department of Medicine and Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Andrea Angeletti
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
| | - Gian Marco Ghiggeri
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
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21
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Amer F, Syed M, Afzal A, Hussain M, Hassan U, Bashir S, Hameed M, Ishtiaq S. IgM and C3 Deposition in Primary Focal Segmental Glomerulosclerosis (FSGS): A Clinical and Histopathological Spectrum. Cureus 2023; 15:e37346. [PMID: 37182061 PMCID: PMC10169510 DOI: 10.7759/cureus.37346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2023] [Indexed: 05/16/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a common renal disorder, characterized by progressive segmental sclerosis of renal glomeruli and clinical symptoms corresponding to proteinuria. Classically, it is not considered to be an antibody-mediated disease, however, IgM and C3 deposition may be seen in a subset of cases of FSGS. The impact of this immune deposition on histopathological features in renal core biopsies, on the urinary biochemical parameters, and the clinical outcomes, has not been previously investigated in our population. The aim of this study is to analyze the aforementioned parameters in patients with primary FSGS having antibody deposition as compared to those who do not have any antibody deposition. Some 155 patients diagnosed with FSGS were retrospectively enrolled in our study. The renal biopsies were reviewed for histopathological features and immunofluorescence (IF) findings of IgM and C3 glomerular deposition. These histological features were then compared with the biochemical parameters as well as the clinical outcomes of patients. The patients were assigned to Groups 1 and 2 based on the IF findings. The IgM and/or C3 glomerular deposition had a low incidence in patients with primary FSGS in our study (28.3%). Patients having IgM and C3 co-deposition had a significantly longer time duration since the onset of their clinical symptoms; active disease duration (42 months vs 22 months, p=0.049). The mean pre-treatment serum creatinine of patients with IgM and C3 co-deposition was 6.00 mg/dL as compared to 3.29 mg/dL in patients with no immune deposition (p=0.037). The immune deposition was associated with higher rates of segmental and global glomerulosclerosis, but this finding along with other evaluated histological parameters did not show statistical significance. The number of patients having IgM and/or C3 deposition and with active steroid use/renal dialysis was similar to patients having no IgM and/or C3 deposition. The IgM and/or C3 deposition in FSGS has a low incidence within and is not associated with any significant differences in histological parameters on renal core biopsies of patients from the Pakistani population. IgM and/or C3 deposition is also associated with a significantly longer duration of active disease and these patients may present with higher pre-treatment serum creatinine. Other biochemical parameters and clinical outcomes appear comparable between the groups based on the available clinical data.
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Affiliation(s)
- Faizan Amer
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | - Madiha Syed
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | | | - Mudassar Hussain
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | - Usman Hassan
- Pathology, Shaukat Khanum Memoiral Cancer Hospital and Research Centre, Lahore, PAK
| | - Shaarif Bashir
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | - Maryam Hameed
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
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22
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Staruschenko A, Ma R, Palygin O, Dryer SE. Ion channels and channelopathies in glomeruli. Physiol Rev 2023; 103:787-854. [PMID: 36007181 PMCID: PMC9662803 DOI: 10.1152/physrev.00013.2022] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 08/15/2022] [Accepted: 08/21/2022] [Indexed: 11/22/2022] Open
Abstract
An essential step in renal function entails the formation of an ultrafiltrate that is delivered to the renal tubules for subsequent processing. This process, known as glomerular filtration, is controlled by intrinsic regulatory systems and by paracrine, neuronal, and endocrine signals that converge onto glomerular cells. In addition, the characteristics of glomerular fluid flow, such as the glomerular filtration rate and the glomerular filtration fraction, play an important role in determining blood flow to the rest of the kidney. Consequently, disease processes that initially affect glomeruli are the most likely to lead to end-stage kidney failure. The cells that comprise the glomerular filter, especially podocytes and mesangial cells, express many different types of ion channels that regulate intrinsic aspects of cell function and cellular responses to the local environment, such as changes in glomerular capillary pressure. Dysregulation of glomerular ion channels, such as changes in TRPC6, can lead to devastating glomerular diseases, and a number of channels, including TRPC6, TRPC5, and various ionotropic receptors, are promising targets for drug development. This review discusses glomerular structure and glomerular disease processes. It also describes the types of plasma membrane ion channels that have been identified in glomerular cells, the physiological and pathophysiological contexts in which they operate, and the pathways by which they are regulated and dysregulated. The contributions of these channels to glomerular disease processes, such as focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, as well as the development of drugs that target these channels are also discussed.
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Affiliation(s)
- Alexander Staruschenko
- Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida
- Hypertension and Kidney Research Center, University of South Florida, Tampa, Florida
- James A. Haley Veterans Hospital, Tampa, Florida
| | - Rong Ma
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, Texas
| | - Oleg Palygin
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Stuart E Dryer
- Department of Biology and Biochemistry, University of Houston, Houston, Texas
- Department of Biomedical Sciences, Tilman J. Fertitta Family College of Medicine, University of Houston, Houston, Texas
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23
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Abstract
Idiopathic nephrotic syndrome often responds to immunosuppressive treatment. Nevertheless, this syndrome-and the drugs used to treat it-remain important causes of patient morbidity. Idiopathic nephrotic syndrome is usually caused by minimal change disease or FSGS, diseases that primarily affect the podocytes. In spite of decades of research, the underlying causes of both diseases remain incompletely understood. There is, however, a large body of observational and experimental data linking the immune system with both minimal change disease and FSGS, including associations with systemic infections and hematologic malignancies. Perhaps most compellingly, many different immunomodulatory drugs are effective for treating idiopathic nephrotic syndrome, including biologic agents that have well-defined immune targets. In fact, the unexpected efficacy of targeted therapeutic agents has provided important new insights into the pathogenesis of these diseases. Given the large number of drugs that are available to deplete or block specific cells and molecules within the immune system, a better understanding of the immunologic causes of idiopathic nephrotic syndrome may lead to better diagnostic and therapeutic approaches.
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Affiliation(s)
- Ruth E. Campbell
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, Colorado
| | - Joshua M. Thurman
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, Colorado
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24
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Morello W, Proverbio E, Puccio G, Montini G. A Systematic Review and Meta-Analysis of the Rate and Risk Factors for Post-transplant Disease Recurrence in Children With Steroid Resistant Nephrotic Syndrome. Kidney Int Rep 2022; 8:254-264. [PMID: 36815113 PMCID: PMC9939313 DOI: 10.1016/j.ekir.2022.10.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 10/26/2022] [Accepted: 10/31/2022] [Indexed: 11/09/2022] Open
Abstract
Introduction Posttransplant disease recurrence is a feared and severe complication in children with steroid resistant nephrotic syndrome (SRNS), but little is known about its incidence. Recent data suggest relapse is exceptional in patients with genetic SRNS, and initial steroid sensitivity may represent a risk factor for recurrence. Methods Systematic review and meta-analysis were performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to describe the post-transplant relapse rate among children with SRNS; as well as the association between recurrence and all potential risk factors, including the presence of causative genetic mutations, initial steroid sensitivity, underlying histology, and gender. The inclusion criteria were as follows: (i) children with SRNS who are undergoing kidney transplant, (ii) available data on post-transplant recurrence, (iii) no patient selection according to the underlying histology, (iv) available data on genetic testing, and (v) prospective or retrospective cohort design. Results Of the 5818 records identified, 8 studies including 581 children with SRNS met the inclusion criteria. Overall posttransplant recurrence rate was 39% (95% confidence interval [CI] 34%-44%). No genetic patient relapsed, whereas the recurrence rate in patients with no causative genetic mutation identified was 61% (95% CI 53%-69%). Children with initial steroid sensitivity were at a higher risk for recurrence with a 1.91 relative risk (RR) (95% CI 1.48-2.46) compared with those with primary SRNS (PSRNS). Gender and histology did not significantly affect relapse rate. Conclusion Post-transplant recurrence is a common event in children with idiopathic non-genetic SRNS, complicating the clinical course in over 60% of patients. The presence of a causative genetic mutation virtually excludes a recurrence. Initial steroid sensitivity is the only other significant risk factor, doubling the risk of relapse.
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Affiliation(s)
- William Morello
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
| | - Emanuele Proverbio
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
| | - Giuseppe Puccio
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
| | - Giovanni Montini
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy,Department of Clinical Sciences and Community Health, University of Milan, Italy,Correspondence: Giovanni Montini, Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milano, Italy.
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Hada I, Shimizu A, Takematsu H, Nishibori Y, Kimura T, Fukutomi T, Kudo A, Ito-Nitta N, Kiuchi Z, Patrakka J, Mikami N, Leclerc S, Akimoto Y, Hirayama Y, Mori S, Takano T, Yan K. A Novel Mouse Model of Idiopathic Nephrotic Syndrome Induced by Immunization with the Podocyte Protein Crb2. J Am Soc Nephrol 2022; 33:2008-2025. [PMID: 35985815 PMCID: PMC9678040 DOI: 10.1681/asn.2022010070] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 07/25/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The cause of podocyte injury in idiopathic nephrotic syndrome (INS) remains unknown. Although recent evidence points to the role of B cells and autoimmunity, the lack of animal models mediated by autoimmunity limits further research. We aimed to establish a mouse model mimicking human INS by immunizing mice with Crb2, a transmembrane protein expressed at the podocyte foot process. METHODS C3H/HeN mice were immunized with the recombinant extracellular domain of mouse Crb2. Serum anti-Crb2 antibody, urine protein-to-creatinine ratio, and kidney histology were studied. For signaling studies, a Crb2-expressing mouse podocyte line was incubated with anti-Crb2 antibody. RESULTS Serum anti-Crb2 autoantibodies and significant proteinuria were detected 4 weeks after the first immunization. The proteinuria reached nephrotic range at 9-13 weeks and persisted up to 29 weeks. Initial kidney histology resembled minimal change disease in humans, and immunofluorescence staining showed delicate punctate IgG staining in the glomerulus, which colocalized with Crb2 at the podocyte foot process. A subset of mice developed features resembling FSGS after 18 weeks. In glomeruli of immunized mice and in Crb2-expressing podocytes incubated with anti-Crb2 antibody, phosphorylation of ezrin, which connects Crb2 to the cytoskeleton, increased, accompanied by altered Crb2 localization and actin distribution. CONCLUSION The results highlight the causative role of anti-Crb2 autoantibody in podocyte injury in mice. Crb2 immunization could be a useful model to study the immunologic pathogenesis of human INS, and may support the role of autoimmunity against podocyte proteins in INS.
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Affiliation(s)
- Ichiro Hada
- Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan
| | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
| | - Hiromu Takematsu
- Department of Molecular Cell Biology, Faculty of Medical Technology, Graduate School of Health Sciences, Fujita Health University, Toyoake, Japan
| | - Yukino Nishibori
- Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan
| | - Toru Kimura
- Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan
| | - Toshiyuki Fukutomi
- Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan
| | - Akihiko Kudo
- Department of Microscopic Anatomy, Kyorin University School of Medicine, Tokyo, Japan
| | - Noriko Ito-Nitta
- Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan
| | - Zentaro Kiuchi
- Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan
| | - Jaakko Patrakka
- KI/AZ Integrated Cardio Metabolic Center, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
| | - Naoaki Mikami
- Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan
| | - Simon Leclerc
- Department of Medicine, Division of Nephrology, Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Yoshihiro Akimoto
- Department of Microscopic Anatomy, Kyorin University School of Medicine, Tokyo, Japan
| | - Yoshiaki Hirayama
- Vaccine & Reagent, R&D Department, Denka Co., Ltd, Gosen-City, Japan
| | - Satoka Mori
- Denka Innovation Center, Denka Co., Ltd, Machida, Japan
| | - Tomoko Takano
- Department of Medicine, Division of Nephrology, Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Kunimasa Yan
- Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan
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Circulating Permeability Factors in Focal Segmental Glomerulosclerosis: In V itro Detection. Kidney Int Rep 2022; 7:2691-2703. [PMID: 36506233 PMCID: PMC9727530 DOI: 10.1016/j.ekir.2022.09.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/12/2022] [Accepted: 09/13/2022] [Indexed: 12/15/2022] Open
Abstract
Introduction The recurrence of proteinuria after kidney transplantation in patients with focal segmental glomerulosclerosis (FSGS) is considered proof of the presence of circulating permeability factors (CPFs). The aim of this study is to demonstrate the presence of plasma CPFs using series of in vitro assays. Methods Podocytes and endothelial cells (glomerular microvascular endothelial cells [GMVECs]) were incubated with plasma from FSGS patients with presumed CPFs in relapse and remission and from steroid-resistant nephrotic syndrome (SRNS), steroid-sensitive nephrotic syndrome (SSNS), membranous nephropathy (MN), and healthy controls (hCtrls). Cell viability, podocyte actin cytoskeleton architecture, and reactive oxygen species (ROS) formation with or without ROS scavenger were investigated by Cell Counting Kit-8 assay, immunofluorescence staining, and CM-H2DCFDA probing, respectively. Results Presumed CPF-containing plasma causes a series of events in podocytes but not in GMVECs. These events include actin cytoskeleton rearrangement and excessive formation of ROS, which results in podocyte loss. These effects were solely observed in response to CPF plasma collected during relapse, but not in response to plasma of hCtrls, or patients with SRNS, SSNS, and MN. The copresence of dimethylthiourea, a scavenger of ROS, abolished the aforementioned effects of CPF plasma. Conclusion We provide a panel of in vitro bioassays to measure podocyte injury and predict the presence of CPFs in plasma of patients with nephrotic syndrome (NS), providing a new framework for monitoring CPF activity that may contribute to future NS diagnostics or used for disease monitoring purposes. Moreover, our findings suggest that the inhibition of ROS formation or facilitating rapid ROS scavenging may exert beneficial effects in patients with CPFs.
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Le Thy PA, Hoang Thi TY, Tran KH, Nguyen HS. Soluble urokinase plasminogen activator receptor (suPAR) and glomerular disease in children: a narrative review. EGYPTIAN PEDIATRIC ASSOCIATION GAZETTE 2022. [DOI: 10.1186/s43054-022-00117-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Focal segmental glomerulosclerosis (FSGS) is a chronic glomerular disease that responds poorly to treatment, with a large proportion of patients progressing to end-stage renal disease in spite of initial aggressive treatment. It is worth emphasizing that the FSGS group has still a high recurrence rate after kidney transplantation. Therefore, understanding the factors involved in the pathogenesis of FSGS will help nephrologists better understand the pathogenesis as well as find out specific targeted therapies. Circulating immune factors have long been implicated in the pathogenesis of FSGS, and recent studies have suggested that soluble urokinase plasminogen activator receptor (suPAR) is one of the good candidates for this hypothesis. The aim of this review study was to analyze the value of suPAR in glomerular disease, especially in clinical studies.
Methods
In this review study, the PubMed database was searched using relevant keywords (suPAR, circulating permeability factors Children, FSGS, and children). Descriptive and cross-sectional studies were reviewed in the current study with the main focuses on the role of suPAR in FSGS, nephrotic syndrome, and the relation to progression of renal failure, especially the research in children.
Results
Overall, 32 studies from different countries were selected. These clinical studies on suPAR have shown the following: (i) the role of suPAR in the diagnosis of FSGS has not yet been confirmed, and (ii) there is strong evidence demonstrating a significant relationship between suPAR and the severity of kidney disease as well as a high value of suPAR in predicting the steroid responsiveness of nephrotic syndrome.
Conclusion
Researching on circulating permeability factors in FSGS is a current trend, which opens new avenues in targeted diagnosis and treatment. suPAR is a promising candidate, and urinary suPAR has also shown advantages over serum suPAR; therefore, more research on this issue is needed in the future.
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Early, Noninvasive Clinical Indicators of Kidney Prognosis in Primary Nephrotic Syndrome: A Retrospective Exploratory Study. Int J Nephrol 2022; 2022:2718810. [PMID: 35983504 PMCID: PMC9381284 DOI: 10.1155/2022/2718810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 07/11/2022] [Indexed: 11/17/2022] Open
Abstract
This retrospective exploratory study aimed to identify early clinical indicators of kidney prognosis in primary nephrotic syndrome (NS). Univariate Cox proportional hazards regression analysis identified clinical parameters in the 2-month period after initiating immunosuppressive therapy (IST); it predicted 40% reduction in the estimated glomerular filtration rate (eGFR) in 36 patients with primary NS. Time-dependent receiver operating characteristic curve analysis was used to evaluate the performance of the predictors for the cumulative incidence of 40% reduction in the eGFR up to 8 years after initiating IST. The mean follow-up period was 71.9 months. The eGFR was reduced by 40% in four patients. Significant predictors for time to 40% reduction in the eGFR were as follows: an increase in the serum soluble urokinase plasminogen activator receptor (s-suPAR) 2 months after initiating IST (Δs-suPAR (2M); hazard ratio (HR) for every 500 pg/mL increase: 1.36, P=0.006), s-suPAR at 2 months after initiating IST (s-suPAR (2M); HR for every 500 pg/mL increase: 1.13, P=0.015), urinary protein-to-creatinine ratio (u-PCR) (u-PCR (2M); HR for every 1.0 g/gCr increase: 2.94, P=0.003), and urinary liver-type fatty acid-binding protein (u-L-FABP) (u-L-FABP (2M); HR for every 1.0 μg/gCr increase: 1.14, P=0.006). All four factors exhibited high predictive accuracy for cumulative incidence of 40% reduction in the eGFR up to 8 years after initiating IST, with areas under the receiver operating characteristic curve of 0.92 for Δs-suPAR (2M), 0.87 for s-suPAR (2M), 0.93 for u-PCR (2M), and 0.93 for u-L-FABP (2M). These findings suggest that Δs-suPAR (2M), s-suPAR (2M), u-PCR (2M), and u-L-FABP (2M) could be useful indicators of initial therapeutic response for predicting kidney prognosis in primary NS.
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Hu H, Li M, Chen B, Guo C, Yang N. Activation of necroptosis pathway in podocyte contributes to the pathogenesis of focal segmental glomerular sclerosis. Clin Exp Nephrol 2022; 26:1055-1066. [PMID: 35925422 DOI: 10.1007/s10157-022-02258-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 07/21/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Focal segmental glomerulosclerosis (FSGS) is characterized by podocyte damage and severe proteinuria. The exact mechanism of podocyte damage and loss remains unclear. Necroptosis, a lytic form of programmed cell death mediated by RIP3 and MLKL, has emerged as an important cell death pattern in multiple tissues and cell types. Necroptosis in FSGS has not been investigated. METHODS Public GEO data regarding podocyte treated with vehicle or adriamycin (ADR) was identified and analyzed. Cultured human podocytes were used to explore the activation of necroptosis upon ADR stimulation. The expression of necroptosis pathway molecules, p-RIP3 and p-MLKL, was examined in the glomeruli and defoliated urinary podocytes of patients with FSGS. The effect of necroptosis inhibition was assessed in ADR-induced glomerulopathy mice using GSK872. RESULTS Publicly available RNA-sequencing data analysis showed that both necroptosis and NLRP3 inflammasome pathway were up-regulated in ADR-injured podocyte. Immunofluorescent staining showed increased expression of p-RIP3 and p-MLKL, the active forms of RIP3 and MLKL, in podocytes of FSGS patients and ADR-induced glomerulopathy mice but not in the normal control. GSK872, an RIP3 kinase inhibitor, significantly inhibited the expression of p-RIP3, p-MLKL and activation of NLRP3 in cultured podocytes treated with ADR. GSK872 treatment of mice with ADR-induced nephropathy resulted in the reduced expression of p-RIP3, p-MLKL, NLRP3 and caspase-1 p20. GSK872 also significantly inhibited the expression of p-MLKL in the podocytes of ADR-induced nephropathy, resulting in the attenuation of proteinuria and renal histological lesions. CONCLUSION Necroptosis pathway might be a valuable target for the treatment of FSGS.
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Affiliation(s)
- Haoqiang Hu
- Department of Nephrology, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523000, China.,Department of Rheumatology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Second Road, Guangzhou, 510080, China
| | - Mengyuan Li
- Department of Rheumatology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Second Road, Guangzhou, 510080, China
| | - Binfeng Chen
- Department of Rheumatology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Second Road, Guangzhou, 510080, China
| | - Chaohuan Guo
- Department of Rheumatology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Second Road, Guangzhou, 510080, China
| | - Niansheng Yang
- Department of Rheumatology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Second Road, Guangzhou, 510080, China.
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Musiała A, Donizy P, Augustyniak-Bartosik H, Jakuszko K, Banasik M, Kościelska-Kasprzak K, Krajewska M, Kamińska D. Biomarkers in Primary Focal Segmental Glomerulosclerosis in Optimal Diagnostic-Therapeutic Strategy. J Clin Med 2022; 11:jcm11123292. [PMID: 35743361 PMCID: PMC9225193 DOI: 10.3390/jcm11123292] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/02/2022] [Accepted: 06/06/2022] [Indexed: 02/01/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) involves podocyte injury. In patients with nephrotic syndrome, progression to end-stage renal disease often occurs over the course of 5 to 10 years. The diagnosis is based on a renal biopsy. It is presumed that primary FSGS is caused by an unknown plasma factor that might be responsible for the recurrence of FSGS after kidney transplantation. The nature of circulating permeability factors is not explained and particular biological molecules responsible for inducing FSGS are still unknown. Several substances have been proposed as potential circulating factors such as soluble urokinase-type plasminogen activator receptor (suPAR) and cardiolipin-like-cytokine 1 (CLC-1). Many studies have also attempted to establish which molecules are related to podocyte injury in the pathogenesis of FSGS such as plasminogen activator inhibitor type-1 (PAI-1), angiotensin II type 1 receptors (AT1R), dystroglycan(DG), microRNAs, metalloproteinases (MMPs), forkheadbox P3 (FOXP3), and poly-ADP-ribose polymerase-1 (PARP1). Some biomarkers have also been studied in the context of kidney tissue damage progression: transforming growth factor-beta (TGF-β), human neutrophil gelatinase-associated lipocalin (NGAL), malondialdehyde (MDA), and others. This paper describes molecules that could potentially be considered as circulating factors causing primary FSGS.
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Affiliation(s)
- Aleksandra Musiała
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland; (H.A.-B.); (K.J.); (M.B.); (K.K.-K.); (M.K.); (D.K.)
- Correspondence: ; Tel.: +48-6-0172-8231
| | - Piotr Donizy
- Department of Clinical and Experimental Pathology, Division of Clinical Pathology, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Hanna Augustyniak-Bartosik
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland; (H.A.-B.); (K.J.); (M.B.); (K.K.-K.); (M.K.); (D.K.)
| | - Katarzyna Jakuszko
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland; (H.A.-B.); (K.J.); (M.B.); (K.K.-K.); (M.K.); (D.K.)
| | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland; (H.A.-B.); (K.J.); (M.B.); (K.K.-K.); (M.K.); (D.K.)
| | - Katarzyna Kościelska-Kasprzak
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland; (H.A.-B.); (K.J.); (M.B.); (K.K.-K.); (M.K.); (D.K.)
| | - Magdalena Krajewska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland; (H.A.-B.); (K.J.); (M.B.); (K.K.-K.); (M.K.); (D.K.)
| | - Dorota Kamińska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland; (H.A.-B.); (K.J.); (M.B.); (K.K.-K.); (M.K.); (D.K.)
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Sun IO, Bae YU, Lee H, Kim H, Jeon JS, Noh H, Choi JS, Doh KO, Kwon SH. Circulating miRNAs in extracellular vesicles related to treatment response in patients with idiopathic membranous nephropathy. J Transl Med 2022; 20:224. [PMID: 35568952 PMCID: PMC9107687 DOI: 10.1186/s12967-022-03430-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 05/05/2022] [Indexed: 12/29/2022] Open
Abstract
Background Extracellular vesicle (EV)-microRNAs (miRNAs) are potential biomarkers for various renal diseases. This study attempted to identify the circulating EV-miRNA signature not only for discriminating idiopathic membranous nephropathy (IMN) from idiopathic nephrotic syndrome (INS), but also to predict the treatment response of patients with IMN. Methods We prospectively enrolled 60 participants, including those with IMN (n = 19) and INS (n = 21) and healthy volunteers (HVs; n = 20) in this study. Using RNA sequencing, we assessed the serum EV-miRNA profiles of all participants. To identify the EV-miRNAs predictive of treatment response in IMN, we also analyzed EV-miRNAs among patients with IMN with and without clinical remission. Results The expression levels of 3 miRNAs differed between IMN patients, INS patients and HVs. In addition, compared to HVs, RNA sequencing revealed differential expression of 77 and 44 EV-miRNAs in patients with IMN without and with remission, respectively. We also identified statistically significant (|fold change ≥ 2, p < 0.05) differences in the expression levels of 23 miRNAs in IMN without remission. Biological pathway analysis of miRNAs in IMN without remission indicated that they are likely involved in various pathways, including renal fibrosis. Conclusion Our study identified EV-miRNAs associated with IMN as well as those associations with therapeutic response. Therefore, these circulating EV-miRNAs may be used as potential markers for the diagnosis and prediction of treatment response in patients with IMN. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03430-7.
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Affiliation(s)
- In O Sun
- Division of Nephrology, Department of Internal Medicine, Presbyterian Medical Center, Jeonju, Republic of Korea
| | - Yun-Ui Bae
- Department of Internal Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Haekyung Lee
- Division of Nephrology, Soonchunhyang University Seoul Hospital, 59 Daesagwan-ro, Youngsan-gu, Seoul, 04401, Republic of Korea
| | - Hyoungnae Kim
- Division of Nephrology, Soonchunhyang University Seoul Hospital, 59 Daesagwan-ro, Youngsan-gu, Seoul, 04401, Republic of Korea
| | - Jin Seok Jeon
- Division of Nephrology, Soonchunhyang University Seoul Hospital, 59 Daesagwan-ro, Youngsan-gu, Seoul, 04401, Republic of Korea
| | - Hyunjin Noh
- Division of Nephrology, Soonchunhyang University Seoul Hospital, 59 Daesagwan-ro, Youngsan-gu, Seoul, 04401, Republic of Korea
| | - Jong-Soo Choi
- Department of Physiology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
| | - Kyung-Oh Doh
- Department of Physiology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea.
| | - Soon Hyo Kwon
- Division of Nephrology, Soonchunhyang University Seoul Hospital, 59 Daesagwan-ro, Youngsan-gu, Seoul, 04401, Republic of Korea.
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Jiao J, Wang L, Ni F, Wang M, Feng S, Gao X, Chan H, Yang X, Lee H, Chi H, Chen X, Wu D, Zhang G, Yang B, Wang A, Yang Q, Wan J, Yu S, Li X, Wang M, Chen X, Mai X, Ruan X, Yang H, Li Q. Whole-exome sequencing of a multicenter cohort identifies genetic changes associated with clinical phenotypes in pediatric nephrotic syndrome. Genes Dis 2022; 9:1662-1673. [PMID: 36157477 PMCID: PMC9485284 DOI: 10.1016/j.gendis.2022.03.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 03/06/2022] [Accepted: 03/22/2022] [Indexed: 11/19/2022] Open
Abstract
Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome (NS) of different etiologies is critical for early clinical guidance. We employed whole-exome sequencing (WES) to detect monogenic causes of NS in a multicenter cohort of 637 patients. In this study, a genetic cause was identified in 30.0% of the idiopathic steroid-resistant nephrotic syndrome (SRNS) patients. Other than congenital nephrotic syndrome (CNS), there were no significant differences in the incidence of monogenic diseases based on the age at manifestation. Causative mutations were detected in 39.5% of patients with focal segmental glomerulosclerosis (FSGS) and 9.2% of those with minimal change disease (MCD). In terms of the patterns in patients with different types of steroid resistance, a single gene mutation was identified in 34.8% of patients with primary resistance, 2.9% with secondary resistance, and 71.4% of children with multidrug resistance. Among the various intensified immunosuppressive therapies, tacrolimus (TAC) showed the highest response rate, with 49.7% of idiopathic SRNS patients achieving complete remission. Idiopathic SRNS patients with monogenic disease showed a similar multidrug resistance pattern, and only 31.4% of patients with monogenic disease achieved a partial remission on TAC. During an average 4.1-year follow-up, 21.4% of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease (ESRD). Collectively, this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients, especially those with primary and/or multidrug resistance.
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Affiliation(s)
- Jia Jiao
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Li Wang
- Department of Nephrology, Chengdu Women and Children Central Hospital, Chengdu, Sichuan 610091, PR China
| | - Fenfen Ni
- Department of Nephrology, Sheen Children's Hospital, Shenzhen, Guangdong 518034, PR China
| | - Mo Wang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Shipin Feng
- Department of Nephrology, Chengdu Women and Children Central Hospital, Chengdu, Sichuan 610091, PR China
| | - Xiaojie Gao
- Department of Nephrology, Sheen Children's Hospital, Shenzhen, Guangdong 518034, PR China
| | - Han Chan
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Xueying Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Hao Lee
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Huan Chi
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Xuelan Chen
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Daoqi Wu
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Gaofu Zhang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Baohui Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Anshuo Wang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Qin Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Junli Wan
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Sijie Yu
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Xiaoqin Li
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Mei Wang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Xiaofeng Chen
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Xianying Mai
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
| | - Xiongzhong Ruan
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, PR China
- John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London WC1E 6BT, United Kingdom
| | - Haiping Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
- Corresponding author.
| | - Qiu Li
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400015, PR China
- Corresponding author.
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Lin DW, Chang CC, Hsu YC, Lin CL. New Insights into the Treatment of Glomerular Diseases: When Mechanisms Become Vivid. Int J Mol Sci 2022; 23:3525. [PMID: 35408886 PMCID: PMC8998908 DOI: 10.3390/ijms23073525] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/18/2022] [Accepted: 03/22/2022] [Indexed: 12/23/2022] Open
Abstract
Treatment for glomerular diseases has been extrapolated from the experience of other autoimmune disorders while the underlying pathogenic mechanisms were still not well understood. As the classification of glomerular diseases was based on patterns of juries instead of mechanisms, treatments were typically the art of try and error. With the advancement of molecular biology, the role of the immune agent in glomerular diseases is becoming more evident. The four-hit theory based on the discovery of gd-IgA1 gives a more transparent outline of the pathogenesis of IgA nephropathy (IgAN), and dysregulation of Treg plays a crucial role in the pathogenesis of minimal change disease (MCD). An epoch-making breakthrough is the discovery of PLA2R antibodies in the primary membranous nephropathy (pMN). This is the first biomarker applied for precision medicine in kidney disease. Understanding the immune system's role in glomerular diseases allows the use of various immunosuppressants or other novel treatments, such as complement inhibitors, to treat glomerular diseases more reasonable. In this era of advocating personalized medicine, it is inevitable to develop precision medicine with mechanism-based novel biomarkers and novel therapies in kidney disease.
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Affiliation(s)
- Da-Wei Lin
- Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi 60069, Taiwan;
| | - Cheng-Chih Chang
- Department of Surgery, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan;
| | - Yung-Chien Hsu
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
| | - Chun-Liang Lin
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Division of Chinese Materia Medica Development, National Research Institute of Chinese Medicine, Taipei 613016, Taiwan
- Kidney Research Center, Chang Gung Memorial Hospital, Taipei 613016, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Chang Gung Memorial Hospital, Kaohsiung 833253, Taiwan
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Chen L, Wu J, Ying D, Jiang M, Xu Y, Mo Y, Rong L, Jiang X. Application of adrenocorticotropic hormone in recurrent focal segmental glomerulosclerosis post-transplantation: A case report and literature review. Pediatr Transplant 2022; 26:e14184. [PMID: 34724313 DOI: 10.1111/petr.14184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/29/2021] [Accepted: 10/20/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND The recurrence rate of focal segmental glomerulosclerosis (FSGS) post-renal transplantation is as high as 30%-50%. However, the pathogenesis is unclear. At present, there is no unified standard for the treatment of recurrent FSGS post-transplantation. Its treatment is full of risks and challenges. METHODS We report a child with recurrent FSGS with massive proteinuria 6~9 g/m2 /day and resistance to plasma exchange (PE) and rituximab (RTX). On the basis of receiving anti-rejection therapy of prednisone, tacrolimus, and mycophenolate mofetil (MMF), we treated the child with adrenocorticotropic hormone (ACTH), and reviewed the literature on the application of ACTH in the recurrence of FSGS post-transplantation. RESULTS After 1 year of treatment with ACTH, the patient's urinary protein decreased and fluctuated between 0.6 and 1.1 g/m2 /day. The albumin (ALB) and cholesterol (CHOL) returned to the normal range. The patient achieved complete remission after 19 months of ACTH treatment and maintained until now. There was no obvious adverse reaction. Literature review showed that up to February 2021, a total of 8 studies showed the use of ACTH in kidney transplant patients, and all the patients in the study achieved remission. CONCLUSIONS ACTH is a potential option for treating recurrent FSGS post-transplantation with fewer side effects and relatively safe for patients. However, further evaluation is needed to better adapt to different populations.
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Affiliation(s)
- Lizhi Chen
- Department of Pediatric Nephrology and Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jingyi Wu
- Department of Pediatric Nephrology and Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Daojing Ying
- Department of Pediatric Nephrology and Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Mengjie Jiang
- Department of Pediatric Nephrology and Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuanyuan Xu
- Department of Pediatric Nephrology and Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ying Mo
- Department of Pediatric Nephrology and Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liping Rong
- Department of Pediatric Nephrology and Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoyun Jiang
- Department of Pediatric Nephrology and Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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The Role of Cytokines in Nephrotic Syndrome. Mediators Inflamm 2022; 2022:6499668. [PMID: 35185384 PMCID: PMC8849808 DOI: 10.1155/2022/6499668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 01/16/2022] [Accepted: 01/27/2022] [Indexed: 12/22/2022] Open
Abstract
Idiopathic nephrotic syndrome (INS) is an important primary glomerular disease characterized by severe proteinuria. Evidence supports a role for T cell dysfunction in the pathogenesis of INS. Glucocorticoids are the primary therapy for INS; however, steroid-resistant NS (SRNS) patients are at a higher risk of drug-induced side effects and harbor poor prognosis. Although the exact mechanism of the resistance is unknown, the imbalances of T helper subtype 1 (Th1), Th2, and regulatory T cells (Tregs) and their cytokines may be involved in the pathogenesis of glucocorticoid responsiveness. Up to now, no confirmed biomarkers have been able to predict SRNS; however, a panel of cytokines may predict responsiveness and identify SRNS patients. Thus, the introduction of distinctive cytokines as novel biomarkers of SRNS enables both preventions of drug-related toxicity and earlier switch to more effective therapies. This review highlights the impacts of T cell population imbalances and their downstream cytokines on response to glucocorticoid responsiveness state in INS.
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Wang S, Zhao F, Li L, Yu Z. Long-term nephrotic syndrome recurrence risk of kidney transplantation in two siblings with ADCK4-associated glomerulopathy. Pediatr Transplant 2022; 26:e14143. [PMID: 34605136 DOI: 10.1111/petr.14143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 08/19/2021] [Accepted: 09/07/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Mutations in the ADCK4 gene cause steroid-resistant nephrotic syndrome (NS), namely ADCK4-associated glomerulopathy. Reportedly, 38.5% of patients with ADCK4-associated glomerulopathy had end-stage renal disease (ESRD) at the time of diagnosis of ADCK4-associated glomerulopathy, requiring renal replacement therapy, such as dialysis and kidney transplantation. However, long-term NS recurrence risk of kidney transplantation in patients with ADCK4-associated glomerulopathy is unknown. METHODS The clinical data and mutations in ADCK4 of two siblings with steroid-resistant NS were collected. The long-term prognosis of the two siblings who received kidney transplantation was evaluated. RESULTS We describe two siblings with ADCK4-associated glomerulopathy who received deceased donor kidney transplantation and showed no clinical evidence of recurrence of NS during more than 10 years of follow-up. CONCLUSIONS This suggests that long-term NS recurrence risk of kidney transplantation is low in patients with ADCK4-associated glomerulopathy who progress to ESRD.
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Affiliation(s)
- Si Wang
- Department of Pediatrics, Dongfang Hospital, Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Feng Zhao
- Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Li Li
- Department of Pediatrics, Dongfang Hospital, Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Zihua Yu
- Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
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Abstract
Nephrotic syndrome (NS) encompasses a variety of disease processes leading to heavy proteinuria and edema. Minimal change disease (MCD) remains the most common primary cause of NS, as well as the most responsive to pharmacologic treatment with often minimal to no chronic kidney disease. Other causes of NS include focal segmental glomerulosclerosis, which follows MCD, and secondary causes, including extrarenal or systemic diseases, infections, and drugs. Although initial diagnosis relies on clinical findings as well as urine and blood chemistries, renal biopsy and genetic testing are important diagnostic tools, especially when considering non-MCD NS. Moreover, biomarkers in urine and serum have become important areas for research in this disease. NS progression and prognosis are variable and depend on etiology, with corticosteroids being the mainstay of treatment. Other alternative therapies found to be successful in inducing and maintaining remission include calcineurin inhibitors and rituximab. Disease course can range from recurrent disease relapse with or without acute kidney injury to end-stage renal disease in some cases. Given the complex pathogenesis of NS, which remains incompletely understood, complications are numerous and diverse and include infections, electrolyte abnormalities, acute kidney injury, and thrombosis. Pediatricians must be aware of the presentation, complications, and overall long-term implications of NS and its treatment.
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Torres DD, Fontò G, Guastamacchia L, Santangelo L, Carbone V, Piscopo G, Spadaccino F, Ranieri E, Netti GS, Giordano M. Therapeutic Approach for Recurrent Focal Segmental Glomerulosclerosis in Pediatric Renal Transplant Recipients: A Single-Center Experience. Blood Purif 2022; 51:847-856. [DOI: 10.1159/000521311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 12/02/2021] [Indexed: 11/19/2022]
Abstract
<b><i>Introduction:</i></b> Recurrence of focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KTx) develops in 40% of patients, leading to graft loss in half of cases. Extracorporeal apheretic treatments, combined with immunosuppressive drugs, seem to be the most promising therapies, but at now limited reports are available, mainly in pediatric patients. <b><i>Objective:</i></b> We aimed to assess the efficacy of immunoadsorption (IA) to treat recurrent FSGS in pediatric patients. <b><i>Methods:</i></b> We report a case series of 4 pediatric patients (aged 4–12 years) followed at our institution for early recurrent FSGS after KTx. FSGS recurrence was treated with early and intensive apheretic treatments IA. <b><i>Results:</i></b> After IA initiation, a partial remission (PR) of proteinuria at 24-month follow-up was achieved only in 1 patient. The others showed a mild reduction of nephrotic proteinuria, without PR, but gained a significant improvement in clinical signs of nephrotic syndrome (reduction of edema, increased serum albumin, and total protein levels). After a median follow-up of 38 (22–48) months, renal function was almost stable over time in all patients, except one who returned to hemodialysis after 22 months. No severe IA-related complications occurred. <b><i>Conclusions:</i></b> According to our clinical experience, IA revealed as a safe and effective therapy to treat patients with recurrent FSGS after KTx and it could maintain stable renal function in 75% of patients.
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Su CT, See DHW, Huang JW. Lipid-Based Nanocarriers in Renal RNA Therapy. Biomedicines 2022; 10:283. [PMID: 35203492 PMCID: PMC8869454 DOI: 10.3390/biomedicines10020283] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 01/27/2023] Open
Abstract
Kidney disease is a multifactorial problem, with a growing prevalence and an increasing global burden. With the latest worldwide data suggesting that chronic kidney disease (CKD) is the 12th leading cause of death, it is no surprise that CKD remains a public health problem that requires urgent attention. Multiple factors contribute to kidney disease, each with its own pathophysiology and pathogenesis. Furthermore, microRNAs (miRNAs) have been linked to several types of kidney diseases. As dysregulation of miRNAs is often seen in some diseases, there is potential in the exploitation of this for therapeutic applications. In addition, uptake of interference RNA has been shown to be rapid in kidneys making them a good candidate for RNA therapy. The latest advancements in RNA therapy and lipid-based nanocarriers have enhanced the effectiveness and efficiency of RNA-related drugs, thereby making RNA therapy a viable treatment option for renal disease. This is especially useful for renal diseases, for which a suitable treatment is not yet available. Moreover, the high adaptability of RNA therapy combined with the low risk of lipid-based nanocarriers make for an attractive treatment choice. Currently, there are only a small number of RNA-based drugs related to renal parenchymal disease, most of which are in different stages of clinical trials. We propose the use of miRNAs or short interfering RNAs coupled with a lipid-based nanocarrier as a delivery vehicle for managing renal disease.
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Affiliation(s)
- Chi-Ting Su
- Department of Medicine, National Taiwan University Cancer Centre, Taipei 10672, Taiwan; (C.-T.S.); (D.H.W.S.)
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Douliu 640, Taiwan
| | - Daniel H. W. See
- Department of Medicine, National Taiwan University Cancer Centre, Taipei 10672, Taiwan; (C.-T.S.); (D.H.W.S.)
| | - Jenq-Wen Huang
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Douliu 640, Taiwan
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Zanoni F, Khairallah P, Kiryluk K, Batal I. Glomerular Diseases of the Kidney Allograft: Toward a Precision Medicine Approach. Semin Nephrol 2022; 42:29-43. [PMID: 35618394 PMCID: PMC9139085 DOI: 10.1016/j.semnephrol.2022.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The continual development of potent immunosuppressive regimens has led to a decreased incidence of acute rejection and improvement of short-term kidney allograft survival. In contrast to acute rejection, glomerular diseases of the kidney allograft are being encountered more frequently and are emerging as leading causes of late kidney allograft failure. Although data on the pathogeneses of glomerular diseases in the kidney allograft are sparse, cumulative evidence suggests that post-transplant glomerular diseases may be the result of inherited predispositions and immunologic triggers. Although studying immunologic signals and performing genome-wide association studies are ideal approaches to tackle glomerular diseases in the kidney allograft, such studies are challenging because of the lack of adequately powered cohorts. In this review, we focus on the most commonly encountered recurrent and de novo glomerular diseases in the kidney allograft. We address the important advances made in understanding the immunopathology and genetic susceptibility of glomerular diseases in the native kidney and how to benefit from such knowledge to further our knowledge of post-transplant glomerular diseases. Defining genomic and immune predictors for glomerular diseases in the kidney allograft would support novel donor-recipient matching strategies and development of targeted therapies to ultimately improve long-term kidney allograft survival.
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Affiliation(s)
- Francesca Zanoni
- Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | | | - Krzysztof Kiryluk
- Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | - Ibrahim Batal
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA,Corresponding Author: Ibrahim Batal MD, Department of Pathology and Cell Biology, Renal Division, Columbia University Irving Medical Center, 630 W 168th street, VC14-238, New York, NY 10032, Phone: 212-305-9669, Fax: 212-342-5380,
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Horinouchi T, Nozu K, Iijima K. An updated view of the pathogenesis of steroid-sensitive nephrotic syndrome. Pediatr Nephrol 2022; 37:1957-1965. [PMID: 35006356 PMCID: PMC9307535 DOI: 10.1007/s00467-021-05401-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 11/01/2021] [Accepted: 11/24/2021] [Indexed: 11/28/2022]
Abstract
Idiopathic nephrotic syndrome is the most common childhood glomerular disease. Most forms of this syndrome respond to corticosteroids at standard doses and are, therefore, defined as steroid-sensitive nephrotic syndrome (SSNS). Immunological mechanisms and subsequent podocyte disorders play a pivotal role in SSNS and have been studied for years; however, the precise pathogenesis remains unclear. With recent advances in genetic techniques, an exhaustive hypothesis-free approach called a genome-wide association study (GWAS) has been conducted in various populations. GWASs in pediatric SSNS peaked in the human leukocyte antigen class II region in various populations. Additionally, an association of immune-related CALHM6/FAM26F, PARM1, BTNL2, and TNFSF15 genes, as well as NPHS1, which encodes nephrin expressed in podocytes, has been identified as a locus that achieves genome-wide significance in pediatric SSNS. However, the specific mechanism of SSNS development requires elucidation. This review describes an updated view of SSNS pathogenesis from immunological and genetic aspects, including interactions with infections or allergies, production of circulating factors, and an autoantibody hypothesis.
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Affiliation(s)
- Tomoko Horinouchi
- grid.31432.370000 0001 1092 3077Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kandai Nozu
- grid.31432.370000 0001 1092 3077Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazumoto Iijima
- Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan. .,Department of Advanced Pediatric Medicine, Kobe University Graduate School of Medicine, Minatojimaminami-machi 1-6-7, Chuo-ku, Kobe, 650-0047, Japan.
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Kidney Transplantation for Focal Segmental Glomerulosclerosis: Can We Prevent Its Recurrence? Personal Experience and Literature Review. J Clin Med 2021; 11:jcm11010093. [PMID: 35011834 PMCID: PMC8745094 DOI: 10.3390/jcm11010093] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 11/17/2022] Open
Abstract
Background: Primary focal segmental glomerulosclerosis (FSGS) is associated with a high risk of recurrence after kidney transplantation with a major risk of graft loss despite preventive or curative treatments. Aim: to assess graft survival in FSGS kidney-transplant recipients and to compare those that had a relapse with those that had no relapse. Patients/Methods: we included 17 FSGS kidney-transplant recipients between January 2000 and January 2020, separated retrospectively into two groups (recurrences: n = 8 patients; no recurrences: n = 9 patients). FSGS recurrence was defined as having proteinuria of ≥3 g/g or urinary creatinine of ≥3 g/day. All patients received an induction therapy; maintenance immunosuppressive therapy at post-transplantation relied on tacrolimus/mycophenolate mofetil/steroids. In order to prevent or treat FSGS recurrence, patients received apheresis sessions plus rituximab. Results: FSGS recurrence rate was 47%. All patients that relapsed with a first graft also relapsed with subsequent grafts. Median time to recurrence was 3 (min: 1; max: 4745) days, despite rituximab/apheresis prophylaxis. Mean age was significantly lower in the relapsers (group 1) than in the non-relapsers (group 2); i.e., 47 ± 11 vs. 58 ± 9 years (p = 0.04). Time to progression to stage 5 chronic kidney disease (CKD) and young age at FSGS diagnosis were lower in group 1 compared to group 2; i.e., 5 (min: 1; max: 26) vs. 2 (min: 1; max: 26) years, and 16 (min: 4; max: 55) vs. 34 (min: 6; max 48) years, respectively. There was no difference between the two groups in terms of progression to CKD stage 5 on the native kidneys, averaging 7 years in both groups (p = 0.99). In group 1, seven patients received rituximab/apheresis prophylaxis, although this did not prevent the recurrence of FSGS. Conclusion: pretransplant prophylaxis with plasmapheresis/rituximab did not appear to reduce the risk of recurrence of primary FSGS on the graft, but could allow remission in the event of recurrence.
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43
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Wei C, Spear R, Hahm E, Reiser J. suPAR, a Circulating Kidney Disease Factor. Front Med (Lausanne) 2021; 8:745838. [PMID: 34692736 PMCID: PMC8526732 DOI: 10.3389/fmed.2021.745838] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/06/2021] [Indexed: 01/08/2023] Open
Abstract
Urokinase plasminogen activator receptor (uPAR) is a multifaceted, GPI-anchored three-domain protein. Release of the receptor results in variable levels of soluble uPAR (suPAR) in the blood circulation. suPAR levels have been linked to many disease states. In this mini-review, we discuss suPAR as a key circulating molecule mediating kidney disease with a particular focus on differently spliced isoforms.
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Affiliation(s)
- Changli Wei
- Department of Medicine, Rush University Medical Center, Chicago, IL, United States
| | - Ryan Spear
- Department of Medicine, Rush University Medical Center, Chicago, IL, United States
| | - Eunsil Hahm
- Department of Medicine, Rush University Medical Center, Chicago, IL, United States
| | - Jochen Reiser
- Department of Medicine, Rush University Medical Center, Chicago, IL, United States
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Tanoue A, Katayama K, Ito Y, Joh K, Toda M, Yasuma T, D'Alessandro-Gabazza CN, Kawachi H, Yan K, Ito M, Gabazza EC, Tryggvason K, Dohi K. Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis. Sci Rep 2021; 11:20556. [PMID: 34654837 PMCID: PMC8519956 DOI: 10.1038/s41598-021-00159-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 10/07/2021] [Indexed: 11/15/2022] Open
Abstract
Crb2 is a cell polarity-related type I transmembrane protein expressed in the apical membrane of podocytes. Knockdown of crb2 causes glomerular permeability defects in zebrafish, and its complete knockout causes embryonic lethality in mice. There are also reports of Crb2 mutations in patients with steroid-resistant nephrotic syndrome, although the precise mechanism is unclear. The present study demonstrated that podocyte-specific Crb2 knockout mice develop massive albuminuria and microhematuria 2-month after birth and focal segmental glomerulosclerosis and tubulointerstitial fibrosis with hemosiderin-laden macrophages at 6-month of age. Transmission and scanning electron microscopic studies demonstrated injury and foot process effacement of podocytes in 6-month aged podocyte-specific Crb2 knockout mice. The number of glomerular Wt1-positive cells and the expressions of Nphs2, Podxl, and Nphs1 were reduced in podocyte-specific Crb2 knockout mice compared to negative control mice. Human podocytes lacking CRB2 had significantly decreased F-actin positive area and were more susceptible to apoptosis than their wild-type counterparts. Overall, this study's results suggest that the specific deprivation of Crb2 in podocytes induces altered actin cytoskeleton reorganization associated with dysfunction and accelerated apoptosis of podocytes that ultimately cause focal segmental glomerulosclerosis.
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Affiliation(s)
- Akiko Tanoue
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Kan Katayama
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
| | - Yugo Ito
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
- Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan
| | - Kensuke Joh
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Masaaki Toda
- Department of Immunology, Mie University Graduate School of Medicine, Mie, Japan
| | - Taro Yasuma
- Department of Immunology, Mie University Graduate School of Medicine, Mie, Japan
| | | | - Hiroshi Kawachi
- Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kunimasa Yan
- Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan
| | - Masaaki Ito
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Esteban C Gabazza
- Department of Immunology, Mie University Graduate School of Medicine, Mie, Japan
| | - Karl Tryggvason
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore
| | - Kaoru Dohi
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
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45
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Rosa-Guerrero P, Leiva-Cepas F, Agüera-Morales M, Navarro-Cabello MD, Rodríguez-Benot A, Torres-De-Rueda A. First Report in the Literature of Biopsy-Proven Noncollapsing Focal Segmental Glomerulosclerosis Relapse in a Second Renal Transplant Presenting With Thrombotic Microangiopathy: A Case Report. Transplant Proc 2021; 53:2747-2750. [PMID: 34627595 DOI: 10.1016/j.transproceed.2021.07.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 07/16/2021] [Indexed: 11/30/2022]
Abstract
Primary focal segmental glomerulosclerosis (FSGS) is a podocytopathy with an irregular response to immunosuppressive therapies. FSGS relapse occurs in 30% to 80% of kidney grafts, and poor survival outcomes include large proteinuria and the nephrotic syndrome's cardinal clinical features. Thrombotic microangiopathy (TMA) is caused by endothelial injury due to complement dysregulation including acute kidney injury, proteinuria, and severe hypertension common renal presentations. Both pathologies have well-described genetic forms, but their relationship remains uncertain. FSGS lesions can be found in kidney biopsy specimens in patients with TMA, and TMA has been reported in patients with collapsing glomerulopathy. However, this combination has not been clearly described in renal transplant recipients. We present the case of a 22-year-old man who received his second kidney allograft and developed an early graft disfunction with nephrotic syndrome and clinical TMA. His background was remarkable for primary, biopsy-confirmed FSGS in childhood, and he started hemodialysis in 2006 and received a living donor kidney graft the same year. He presented with a FSGS relapse with malignant hypertension and seizures in the first posttransplant month and had an irregular response to plasma exchange and rituximab, and dialysis was reinitiated 10 years later. A total of 3 biopsies were performed after his second kidney transplant showing the evolution of a FSGS relapse with histologic and clinical TMA in the absence of identified genetic mutations. Partial responses to treatments with plasma exchange, eculizumab, and rituximab were obtained, but the allograft was lost after 26 months. This case is the first report of concomitant FSGS and TMA in a renal transplant recipient.
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Affiliation(s)
- Pedro Rosa-Guerrero
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Córdoba, Spain; Department of Nephrology, Reina Sofía University Hospital, Córdoba, Spain.
| | - Fernando Leiva-Cepas
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Córdoba, Spain; Department of Pathology, Reina Sofía University Hospital, Córdoba, Spain
| | - Marisa Agüera-Morales
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Córdoba, Spain; Department of Nephrology, Reina Sofía University Hospital, Córdoba, Spain
| | - María Dolores Navarro-Cabello
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Córdoba, Spain; Department of Nephrology, Reina Sofía University Hospital, Córdoba, Spain
| | - Alberto Rodríguez-Benot
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Córdoba, Spain; Department of Nephrology, Reina Sofía University Hospital, Córdoba, Spain
| | - Alvaro Torres-De-Rueda
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Córdoba, Spain; Department of Nephrology, Reina Sofía University Hospital, Córdoba, Spain; Asociación Medicina e Investigación (AMI), Córdoba, Spain
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46
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Cara-Fuentes G, Smoyer WE. Biomarkers in pediatric glomerulonephritis and nephrotic syndrome. Pediatr Nephrol 2021; 36:2659-2673. [PMID: 33389089 DOI: 10.1007/s00467-020-04867-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/16/2020] [Accepted: 11/18/2020] [Indexed: 12/21/2022]
Abstract
Glomerular diseases are often chronic or recurring and thus associated with a tremendous physical, psychological, and economic burden. Their etiologies are often unknown, and their pathogeneses are frequently poorly understood. The diagnoses and management of these diseases are therefore based on clinical features, traditional laboratory markers, and, often, kidney pathology. However, the clinical presentation can be highly variable, the kidney pathology may not establish a definitive diagnosis, and the therapeutic responses and resulting clinical outcomes are often unpredictable. To try to address these challenges, significant research efforts have been made over the last decade to identify potential biomarkers that can help clinicians optimize the diagnosis and prognosis at clinical presentation, as well as help predict long-term outcomes. Unfortunately, these efforts have to date only identified a single biomarker for glomerular disease that has been fully validated and developed for widespread clinical use (anti-PLA2R antibodies to diagnose membranous nephropathy). In this manuscript, we review the definitions and development of biomarkers, as well as the current knowledge on both historical and novel candidate biomarkers of glomerular disease, with an emphasis on those associated with idiopathic nephrotic syndrome.
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Affiliation(s)
- Gabriel Cara-Fuentes
- Department of Pediatrics, Division of Pediatric Nephrology, University of Colorado, 12700 E 19th Ave, R2 building, Room 7420D, Aurora, CO, 80045, USA.
| | - William E Smoyer
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
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47
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Lanaret C, Anglicheau D, Audard V, Büchler M, Caillard S, Couzi L, Malvezzi P, Mesnard L, Bertrand D, Martinez F, Pernin V, Ducloux D, Poulain C, Thierry A, Del Bello A, Rerolle JP, Greze C, Uro-Coste C, Aniort J, Lambert C, Bouvier N, Schvartz B, Maillard N, Sayegh J, Oniszczuk J, Morin MP, Legendre C, Kamar N, Heng AE, Garrouste C. Rituximab for recurrence of primary focal segmental glomerulosclerosis after kidney transplantation: Results of a nationwide study. Am J Transplant 2021; 21:3021-3033. [PMID: 33512779 DOI: 10.1111/ajt.16504] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 01/15/2021] [Accepted: 01/15/2021] [Indexed: 01/25/2023]
Abstract
Rituximab (RTX) therapy for primary focal segmental glomerulosclerosis recurrence after kidney transplantation (KT) has been extensively debated. We aimed to assess the benefit of adding RTX to plasmapheresis (PP), corticosteroids, and calcineurin inhibitors (standard of care, SOC). We identified 148 adult patients who received KT in 12/2004-12/2018 at 21 French centers: 109 received SOC (Group 1, G1), and 39 received immediate RTX along with SOC (Group 2, G2). In G1, RTX was introduced after 28 days of SOC in the event of failure (G1a, n = 19) or PP withdrawal (G1b, n = 12). Complete remission (CR) was achieved in 46.6% of patients, and partial remission (PR) was achieved in 33.1%. The 10-year graft survival rates were 64.7% and 17.9% in responders and nonresponders, respectively. Propensity score analysis showed no difference in CR+PR rates between G1 (82.6%) and G2 (71.8%) (p = .08). Following the addition of RTX (G1a), 26.3% of patients had CR, and 31.6% had PR. The incidence of severe infections was similar between patients treated with and without RTX. In multivariable analysis, infection episodes were associated with hypogammaglobulinemia <5 g/L. RTX could be used in cases of SOC failure or remission for early discontinuation of PP without increasing the risk of infection.
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Affiliation(s)
- Camille Lanaret
- Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
| | - Dany Anglicheau
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Vincent Audard
- Assistance Publique des Hôpitaux de Paris (AP-HP, Service de Néphrologie et Transplantation Centre de Référence Maladie Rare «Syndrome Néphrotique Idiopathique», Hôpitaux Universitaires Henri-Mondor, Univ Paris Est Créteil, INSERM, IMRB, Créteil, France
| | - Mathias Büchler
- Service de Néphrologie et Immunologie Clinique, CHRU de Tours, Tours, France
| | - Sophie Caillard
- Service de Néphrologie, University Hospital, Strasbourg, France
| | - Lionel Couzi
- Service de Néphrologie, Transplantation, Dialyse et Aphérèses, CHU de Bordeaux, Bordeaux, France
| | - Paolo Malvezzi
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
| | - Laurent Mesnard
- Assistance Publique des Hôpitaux de Paris, Hôpital Universitaire Tenon, Urgences Néphrologiques et Transplantation Rénale, Université de Paris, Paris, France
| | | | - Franck Martinez
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Vincent Pernin
- Service de Néphrologie, Dialyse et Transplantation, Hôpital Lapeyronie, CHU Montpellier, Montpellier, France
| | - Didier Ducloux
- Service de Néphrologie, Dialyse et Transplantation, CHU Besançon, Besançon, France
| | - Coralie Poulain
- Service de Néphrologie-Médecine Interne-Dialyse-Transplantation, CHU d'Amiens, Amiens, France
| | - Antoine Thierry
- Service de Néphrologie-Hémodialyse-Transplantation Rénale, CHU de Poitiers, Poitiers, France
| | - Arnaud Del Bello
- Département de Néphrologie et Transplantation d'Organes, CHU Toulouse, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | - Jean P Rerolle
- Service de Néphrologie, Dialyse et Transplantation, CHU Limoges, Limoges, France
| | - Clarisse Greze
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie, Hôpital Universitaire Bichat-Claude-Bernard, Université de Paris, Paris, France
| | - Charlotte Uro-Coste
- Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
| | - Julien Aniort
- Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
| | - Céline Lambert
- Unité de Biostatistiques (DRCI, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Nicolas Bouvier
- Service de Néphrologie et Transplantation, CHU Caen, Caen, France
| | | | - Nicolas Maillard
- Service de Néphrologie et Transplantation, CHU Saint-Etienne, Saint-Etienne, France
| | - Johnny Sayegh
- Service de Néphrologie-Dialyse-Transplantation, CHU Angers, Angers, France
| | - Julie Oniszczuk
- Assistance Publique des Hôpitaux de Paris (AP-HP, Service de Néphrologie et Transplantation Centre de Référence Maladie Rare «Syndrome Néphrotique Idiopathique», Hôpitaux Universitaires Henri-Mondor, Univ Paris Est Créteil, INSERM, IMRB, Créteil, France
| | | | - Christophe Legendre
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Nassim Kamar
- Département de Néphrologie et Transplantation d'Organes, CHU Toulouse, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | - Anne E Heng
- Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
| | - Cyril Garrouste
- Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
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48
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De Souza L, Prunster J, Chan D, Chakera A, Lim WH. Recurrent glomerulonephritis after kidney transplantation: a practical approach. Curr Opin Organ Transplant 2021; 26:360-380. [PMID: 34039882 DOI: 10.1097/mot.0000000000000887] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW This review will provide a practical approach in the assessment of kidney failure patients with primary glomerulonephritides (GN) being considered for kidney transplantation, focusing on high-risk subtypes of immunoglobulin A nephropathy, focal segmental glomerulosclerosis, idiopathic membranous glomerulonephritis and membranoproliferative glomerulonephritis. RECENT FINDINGS Recurrent glomerulonephritis remains one of the most common causes of allograft loss in kidney transplant recipients. Although the epidemiology and clinical outcomes of glomerulonephritis recurrence occurring after kidney transplantation are relatively well-described, the natural course and optimal treatment strategies of recurrent disease in kidney allografts remain poorly defined. With a greater understanding of the pathophysiology and treatment responses of patients with glomerulonephritis affecting the native kidneys, these discoveries have laid the framework for the potential to improve the management of patients with high-risk glomerulonephritis subtypes being considered for kidney transplantation. SUMMARY Advances in the understanding of the underlying immunopathogenesis of primary GN has the potential to offer novel therapeutic options for kidney patients who develop recurrent disease after kidney transplantation. To test the efficacy of novel treatment options in adequately powered clinical trials requires a more detailed understanding of the clinical and histological characteristics of kidney transplant recipients with recurrent glomerulonephritis.
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Affiliation(s)
- Laura De Souza
- Department of Renal Medicine, Cairns Hospital, Cairns North, Queensland
| | - Janelle Prunster
- Department of Renal Medicine, Cairns Hospital, Cairns North, Queensland
| | - Doris Chan
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth
| | - Aron Chakera
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth
| | - Wai H Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth
- Medical School, University of Western Australia, Crawley, Western Australia, Australia
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49
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Srivastava T, Joshi T, Heruth DP, Rezaiekhaligh MH, Garola RE, Zhou J, Boinpelly VC, Ali MF, Alon US, Sharma M, Vanden Heuvel GB, Mahajan P, Priya L, Jiang Y, McCarthy ET, Savin VJ, Sharma R, Sharma M. A mouse model of prenatal exposure to Interleukin-6 to study the developmental origin of health and disease. Sci Rep 2021; 11:13260. [PMID: 34168254 PMCID: PMC8225793 DOI: 10.1038/s41598-021-92751-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Systemic inflammation in pregnant obese women is associated with 1.5- to 2-fold increase in serum Interleukin-6 (IL-6) and newborns with lower kidney/body weight ratio but the role of IL-6 in increased susceptibility to chronic kidney (CKD) in adult progeny is not known. Since IL-6 crosses the placental barrier, we administered recombinant IL-6 (10 pg/g) to pregnant mice starting at mid-gestation yielded newborns with lower body (p < 0.001) and kidney (p < 0.001) weights. Histomorphometry indicated decreased nephrogenic zone width (p = 0.039) with increased numbers of mature glomeruli (p = 0.002) and pre-tubular aggregates (p = 0.041). Accelerated maturation in IL-6 newborns was suggested by early expression of podocyte-specific protein podocin in glomeruli, increased 5-methyl-cytosine (LC–MS analysis for CpG DNA methylation) and altered expression of certain genes of cell-cycle and apoptosis (RT-qPCR array-analysis). Western blotting showed upregulated pJAK2/pSTAT3. Thus, treating dams with IL-6 as a surrogate provides newborns to study effects of maternal systemic inflammation on future susceptibility to CKD in adulthood.
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Affiliation(s)
- Tarak Srivastava
- Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, 2401 Gillham Road, Kansas City, MO, 64108, USA. .,Midwest Veterans' Biomedical Research Foundation (MVBRF), Kansas City, MO, USA. .,Department of Oral and Craniofacial Sciences, University of Missouri at Kansas City-School of Dentistry, Kansas City, MO, USA.
| | - Trupti Joshi
- Department of Health Management and Informatics and MU Informatics Institute, University of Missouri, Columbia, MO, USA.,Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO, USA.,Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.,MU Data Science and Informatics Institute, University of Missouri, Columbia, MO, USA
| | - Daniel P Heruth
- Children's Mercy Research Institute, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, USA
| | - Mohammad H Rezaiekhaligh
- Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, 2401 Gillham Road, Kansas City, MO, 64108, USA
| | - Robert E Garola
- Department of Pathology and Laboratory Medicine, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, USA
| | - Jianping Zhou
- Midwest Veterans' Biomedical Research Foundation (MVBRF), Kansas City, MO, USA.,Kansas City VA Medical Center, Kansas City, MO, USA
| | - Varun C Boinpelly
- Midwest Veterans' Biomedical Research Foundation (MVBRF), Kansas City, MO, USA.,Kansas City VA Medical Center, Kansas City, MO, USA
| | - Mohammed Farhan Ali
- Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, 2401 Gillham Road, Kansas City, MO, 64108, USA
| | - Uri S Alon
- Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, 2401 Gillham Road, Kansas City, MO, 64108, USA
| | - Madhulika Sharma
- Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Gregory B Vanden Heuvel
- Department of Biomedical Sciences, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
| | - Pramod Mahajan
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Drake University, Des Moines, IA, USA
| | - Lakshmi Priya
- Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, 2401 Gillham Road, Kansas City, MO, 64108, USA
| | - Yuexu Jiang
- Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO, USA.,Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Ellen T McCarthy
- Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Virginia J Savin
- Kansas City VA Medical Center, Kansas City, MO, USA.,Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Ram Sharma
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Mukut Sharma
- Midwest Veterans' Biomedical Research Foundation (MVBRF), Kansas City, MO, USA.,Kansas City VA Medical Center, Kansas City, MO, USA.,Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
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50
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Gene Expression as a Guide to the Development of Novel Therapies in Primary Glomerular Diseases. J Clin Med 2021; 10:jcm10112262. [PMID: 34073694 PMCID: PMC8197155 DOI: 10.3390/jcm10112262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/10/2021] [Accepted: 05/19/2021] [Indexed: 11/17/2022] Open
Abstract
Despite improvements in understanding the pathogenic mechanisms of primary glomerular diseases, therapy still remains nonspecific. We sought to identify novel therapies targeting kidney-intrinsic injury of distinct primary glomerulonephritides through computational systems biology approaches. We defined the unique transcriptional landscape within kidneys from patients with focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), membranous nephropathy (MN) and thin basement membrane nephropathy (TBMN). Differentially expressed genes were functionally annotated with enrichment analysis, and distinct biological processes and pathways implicated in each primary glomerular disease were uncovered. Finally, we identified novel drugs and small-molecule compounds that may reverse each glomerulonephritis phenotype, suggesting they should be further tested as precise therapy in primary glomerular diseases.
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